Genetics & Clinical Cohorts

遗传学

• 批准号: 10653904
• 负责人: Sarah Jane Dunstan
• 金额: $ 49.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653904
• 关键词: Aftercare; Bacterial Genes; Bacterial Genome; Cellular biology; Cessation of life; Cities; Clinical; Clinical Data; Clinical Research; Collection; Communities; Data; Data Set; Disease; Disease Outcome; Disease model; Epidemic; Epidemiology; Evolution; Future; Genes; Genetic; Genetic Determinism; Genetic Variation; Genomics; Household; Human; Immunology; In Vitro; Individual; Investigation; Knowledge; Link; M. tuberculosis genome; Measurement; Medical Genetics; Meningeal Tuberculosis; Mutation; Mycobacterium tuberculosis; Observational Study; Outcome; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Pulmonary Tuberculosis; Randomized Controlled Clinical Trials; Research; Research Personnel; Resistance; Sampling; Signal Transduction; Sputum; System; Technology; Treatment Failure; Tuberculosis; Uganda; Vaccines; Variant; Vietnam; bacterial genetics; bioinformatics tool; candidate identification; clinical care; clinical phenotype; cohort; data resource; design; epidemiologic data; epidemiology study; follow-up; gene discovery; genetic variant; genomic data; genomic variation; human disease; in vivo Model; indexing; innovation; multidisciplinary; novel therapeutics; novel vaccines; participant enrollment; pathogen; pathogen genomics; point of care testing; response; tool; transmission process

To achieve a 95% reduction of TB deaths by 2035 the WHO END-TB strategy states that critical introduction of new tools, such as a vaccine, drugs and treatment regimes, and a point-of-care test are required. New tools to eliminate TB are reliant on new knowledge of TB. Here we are utilizing genomic technology to interrogate pathogen and host genomic variation in TB to advance our fundamental understanding of TB which is critically required to drive innovation for the design of new vaccines and drugs to control the TB epidemic. We will utilize our extensive clinical, epidemiological and genetic cohorts from Vietnam and Uganda which have been complied over the last 2 decades, to discover genetic determinants of TB disease, progression and outcome in humans and M.tuberculosis. We aim to 1/ identify genetic determinants of active pulmonary TB disease in humans and M.tb, 2/ identify genetic determinants in humans and M.tb associated with bacterial burden and poor disease outcome 3/ identify bacterial variants associated with transmission, using evolutionary and epidemiological signatures of transmission. In aims 1 and 2 we will utilize a paired host and pathogen genomic dataset from a large cohort of pulmonary TB patients, and analyze both host and pathogen genomic data individually and in combination. In these aims we will investigate host and pathogen gene variants associated with TB disease and clinical endpoints, as well as with “intermediate phenotypes” such as host control of bacterial replication, bacterial survival in the host, and bacterial clearance. In aim 3 we will use bacterial genome sequence to identify Mtb gene variants contributing to disease transmissibility by 1/ interrogating genomic signals of evolution and 2/ by utilizing epidemiological data of households with low and high TB transmission. The aims of core A Genetics will deliver gene discoveries to the 3 projects for functional analysis, while functional candidates identified in the 3 projects using in vitro and in vivo models will be assessed within our clinical cohorts to bridge the “investigative” gap between TB disease models and human TB disease. Through human and bacterial genomics, the outcome of core A will be the identification of key mechanisms in the response to Mtb infection, Mtb transmissibility, TB susceptibility and disease outcome. This research will have impact by advancing our fundamental understanding of TB which is essential to drive innovation for the future control of the TB epidemic.

为实现到2035年将结核病死亡人数减少95%的目标，世卫组织终止结核病战略指出，关键是采用